PROJECT 1- Summary: Gastric adenocarcinoma is one of the leading global causes of cancer mortality, with marked geographic variation in incidence rates. Infection with Helicobacter pylori, and cagA+ strains, specifically, are well- recognized risk factors, but are highly prevalent in Latin American populations, and insufficient to delineate at- risk patients. There is a critical need to develop biomarkers for the identification of individuals who are at highest risk for disease progression from chronic gastritis and precancerous (atrophy, intestinal metaplasia) stages to adenocarcinoma. Previously, this project has studied a unique long-term cohort of Colombian subjects in chemoprevention trial which included H. pylori eradication, and we have recently demonstrated that the mismatch between genetic ancestries of the human host and the infecting H. pylori strain (disrupted co- evolution) is associated with gastric cancer risk. Further, we have found that specific host gene methylation abnormalities in gastric mucosae may be markers of progression risk. We hypothesize that cancer risk is determined by H. pylori and human host genetic interactions, and also is predicted by specific host gene methylation alterations. We will utilize our highly productive and cost-effective research infrastructures in Colombia and Central America to facilitate studies in these high risk populations. Our specific aims are: (1) To determine the rate of histologic progression of high risk subjects in the long-term Colombian chemoprevention cohort. We will perform regular subject household follow-up over the next 5 years and one additional endoscopic assessment of subjects at year 24, with a focus on highest risk subjects with precancerous lesions. We will determine rates of progression to dysplasia and carcinoma and the effect of duration and timing of H. pylori infection-free period, re-infection and strain differences on histopathology. (2) To determine if H. pylori? human genetic ancestry interactions are a generalizable determinant of cancer risk in high and low risk populations in Central America, as we have observed in Colombia. We will enroll subjects with a range of gastric lesions ranging from chronic gastritis to adenocarcinoma from the high risk Central American mountainous (Mestizo) region and two low risk coastal regions, namely Pacific (Mestizo) and Caribbean (African) populations. We will characterize human and H. pylori genetic ancestry with high-density genetic arrays and whole genome sequencing, respectively, using global diagnosis and the validated histopathology score as the outcome measures. (3) To determine if DNA promoter methylation levels of specific genes are associated with the risk of progression in the Colombian cohort. We will quantify DNA methylation of specific gene promoters at baseline and year 16 as predictors of histopathologic progression at years 20 and 24. We will also explore the influence of human and bacterial genetic ancestry on methylation in the Central America patient group. We expect these studies to provide novel tools to identify individuals with elevated risk for gastric cancer.